The experiments below are designed to address the relationship between the SIV and METH in the induction of alterations in CNS function. We hypothesize that METH and HIV induce convergent cellular processes in the CNS to induce neuropathogenesis. During the life and at autopsy, we have chosen measures to examine these processes and the changes they produce. Since viral load has significant consequences on the course of AIDS and likely neuroAIDS, we will assess virus in the periphery and CNS, as well as determining the CTL response, critical in controlling viral load. Since METH is known to affect neurons and monoamine neurotransmitter systems in the striatum, quantification of neurons and neurochemicals will assess our hypothesis that SIV synergizes with METH in inducing damage to the CNS. In Aim 1, we hypothesize that METH administration surrounding the early phase of SIV infection will lead to increased damage to the CNS and effects on the crucial viral-host interaction setting the course of disease. Since the CNS itself is both infected and affected early following inoculation, changes occurring during the acute injection period may dramatically alter CNS disease. METH administration is predicted to lead to more profound, or quicker development of, SIV-induced abnormalities. During life, a longitudinal study of selected electrophysiological, physiological, behavioral, viral, monoamine metabolite and immune parameters will be performed. This aim will model an active METH user who becomes HIV infected. In Aim 2, we hypothesize that METH administration in the setting of chronic injection can work through numerous mechanisms to augment the CNS deficits induced by SIV infection. Among these are making the CNS more susceptible to damage through neurotoxic effects, affecting viral replication kinetics, or altering immune cell trafficking to the CNS. Here we will treat with METH for two periods following stable establishment of SIV infection. In this manner we will model an HIV-infected individual who uses METH. The first period of METH administration will allow us to determine the effects of measures of physiology, CNS function, and viral/host interactions. The second will allow the same determinations for repeat METH use, and CNS tissue analysis at the end of the second METH period will allow direct examination of the pathological consequences of recent METH use, in the setting of SIV injection and a history of METH use.